7. Project Summary/Abstract This application is being submitted to PA-18-591 in accordance with NOT-OD-18-195. Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer disease (AD) in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. Imaging studies reveal early neuropathology within the striatum and frontal lobes. Given these regions are involved in motor and cognitive function, we hypothesize that gait will be associated with changes in cognition and prodromal dementia. We will follow up with an initial cohort of DS individuals who had gait assessed three years ago to assess whether the degree of change in gait associates with prodromal dementia. Next, we will use a dual-task gait paradigm to elucidate subtle gait impairment and compare spatial and temporal gait characteristics from people with DS over a wide range of ages. Finally, we will use structural neuroimaging to identify underlying neural substrates associated with changes in gait and prodromal dementia. Determining whether gait indicates early pathogenesis of AD in DS will initiate early treatment, improving quality of life. Furthermore, earlier detection of prodromal dementia will facilitate research investigating pathogenesis and subsequently may provide novel targets for a preventative approach to slow or halt the development of AD neuropathology.